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Pfizer is one
of a handful of companies that have fully embraced
biomarker development. Robinson-Gravatt noted that two
or three years ago, the firm decided that "all projects
have a biomarker operating plan." Biomarker-based
decision-making is an internal best practice for
project teams, she told the DIA meeting. "Teams [a]re
expected to define biomarker approaches and the
tradeoffs within their budgets and to bring those
biomarker projects forward and use them for
decision-making."
While at
first biomarkers were used for early decision-making
internally, biomarkers and their use have advanced. Now
the company is dealing with "uncertainties" involved
with full validation of biomarkers, Robinson-Gravatt
said. Pfizer has recognized the value of the consortium
approach when trying to validate biomarkers,
collaborating with other stakeholders to obtain
regulatory acceptance for specific biomarkers and their
use.
As an
example, she outlined Pfizer's efforts in identifying
biomarkers for vascular injury. After years of
research, in 2004 the company brought that data
together and created a formal organization, a
"high-level project mound ... for evaluating projects
and bringing them down to the level of clinical
validation," Robinson-Gravatt said.
Pfizer's
search for non-invasive biomarkers for vascular injury
has included in vitro studies, genomic expression
profiling, proteomic profiling and metabonomic
profiling. A problem with this toxicity is that there
appears to be no link to any particular structure or
target, Robinson-Gravatt said. A complex dataset was
submitted to FDA under the agency's Voluntary Genomic
Data Submission program in order to obtain agency input
on interpreting some of the data ('The Pink Sheet'
Dec. 4, 2006, p. 18).
During the
past three to four years, Pfizer has conducted 40-50
preclinical studies in several species with numerous
compounds having different mechanisms to identify
biomarkers of vascular injury. Fifty potential
biological indicators of vascular impact have been
narrowed down to 15. The firm now has a dedicated
budget and eight full-time equivalents working on the
vascular injury biomarker project.
"It was a
huge internal effort and it got us to a point where we
got a number of well-rationalized markers but ... the
story ... could not be brought to a conclusion,"
Robinson-Gravatt said. The consortium now has a working
group devoted to biomarkers for vascular injury.
Pfizer's
research efforts in biomarkers have also produced some
well-rationalized biomarkers for hepatotoxicity,
Robinson-Gravatt reported.
Pfizer has
collaborated with Oxford GlycoSciences to identify
drug-associated alterations in the expression of
hepatic proteins. Three biomarkers - PON-1, malate
dehydrogense and purine nucleoside phosphorylase - have
been confirmed to be associated with altered liver
structure or function, using histopathologic and
clinical chemistry. A more than three year effort,
including rat studies with four toxicants, has produced
markers useful for internal decision making. The PSTC
also has a working group on hepatotoxicity, which is
expected to be the consortium's next submission to
FDA.
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